Carbocyclic derivatives

ABSTRACT

The present invention relates to compounds of formula (I) 
     
         ArCH.sub.2 R.sup.1                                         (I) 
    
     or a monomethyl or monoethyl ether thereof (the compound of formula (I) including these ethers may contain no more than 30 carbon atoms in total); ethers, esters, thereof; acid addition salts thereof; wherein Ar is a C 15-18  fused tetracarbocyclic ring system containing 3 or 4 aromatic rings or a C 17-22  fused pentacarbocyclic ring system containing 4, or 5 aromatic rings, or a substituted derivative thereof; the ring system Ar should be planar or deviate only slightly from planarity. Thus, the ring system contains a maximum of two non-aromatic carbon atoms which may be in the same ring, in which case they are adjacent, or in different rings; 
     Ar is not perylene, fluoranthene, chrysene, pyrene, or triphenylene; 
     R 1  contains not more than eight carbon atoms and is a group ##STR1##  wherein m is 0 or 1; 
     R 5  is hydrogen; 
     R 6  and R 7  are the same or different and each is hydrogen or C 1-5  alkyl optionally substituted by hydroxy; 
     R 8  and R 9  are the same or different and each is hydrogen or C 1-3  alkyl; ##STR2##  is a five- or six-membered saturated carbocyclic ring; R 10  is hydrogen, methyl or hydroxymethyl; 
     R 11 , R 12  and R 13  are the same or different and each is hydrogen or methyl; 
     R 14  is hydrogen, methyl, hydroxy, or hydroxymethyl.

This is a continuation of application Ser. No. 801,060 filed Nov. 22,1985, now abandoned, which is a continuation-in-part of application Ser.No. 673,531 filed Nov. 20, 1984, now abandoned.

The present invention relates to polycyclic alkanol derivatives whichhave been found to have biocidal activity. More specifically theinvention concerns aminoalkanol derivatives containing a polycarbocyclicring system, methods for the synthesis thereof, pharmaceuticalformulations thereof, novel intermediates therefor, and the use thereofas biocidal agents, particularly antitumor agents.

Accordingly, in a first aspect, the present invention provides acompound of the formula (I)

    ArCH.sub.2 R.sup.1                                         (I)

or a monomethyl or monoethyl ether thereof (the compond of formula (I)including these ethers may contain no more than 30 carbon atoms intotal); ethers, esters thereof; acid addition salts thereof; wherein Aris a C₁₅₋₁₈ fused tetracarbocyclic ring system containing 3 or 4aromatic rings or a C₁₇₋₂₂ fused pentacarbocyclic ring system containing4 or 5 aromatic rings optionally substituted by one or two substituents(the substituents will contain not more than four carbon atoms in totalwhen taken together being the same or different and are selected fromhalogen; cyano; C₁₋₄ alkyl or C₁₋₄ alkoxy, each optionally substitutedby hydroxy or C₁₋₂ alkoxy; halogen substituted C₁₋₂ alkyl or C₁₋₂alkoxy; a group S(O)_(n) R² wherein n is an integer 0, 1 or 2 and R² isC₁₋₂ alkyl optionally substituted by hydroxy or C₁₋₂ alkoxy; or the ringsystem is optionally substituted by a group NR³ R⁴ containing not morethan 5 carbon atoms wherein R³ and R⁴ are the same or different and eachis a C₁₋₃ alkyl group or NR³ R⁴ forms a five- or six-memberedheterocyclic ring optionally containing one or two additionalheteroatoms); the ring system Ar should be planar or deviate onlyslightly from planarity. Thus, the ring system contains a maximum of twononaromatic carbon atoms which may be in the same ring, in which casethey are adjacent, or in different rings;

Ar is not perylene, fluoranthene, chrysene, pyrene, or triphenylene,

R¹ contains not more than eight carbon atoms and is a group ##STR3##wherein m is 0 or 1; R⁵ is hydrogen;

R⁶ and R⁷ are the same or different and each is hydrogen or C₁₋₅ alkyloptionally substituted by hydroxy;

R⁸ and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;##STR4## is a five- or six-membered saturated carbocyclic ring; R¹⁰ ishydrogen, methyl or hydroxymethyl;

R¹¹, R¹² and R¹³ are the same or different and each is hydrogen ormethyl;

R¹⁴ is hydrogen, methyl, hydroxy, or hydroxymethyl.

Suitably ArCH₂ R¹ or a monomethyl or monethyl ether thereof contains notmore than 28 carbon atoms in total. Suitably, there is a maximum of onenon-aromatic carbon in the ring system.

Ar is suitably naphthacenyl, benz[a]anthracenyl, benzo[a]pyrenyl,aceanthrylenyl, aceanthrenyl, 7H-benzo[c]fluoranthenyl,11H-benzo[a]fluoranthenyl, acephenanthrylenyl,4,5-dihydroacephenanthrylenyl, benzo[c]phenanthrenyl,4H-cyclopenta[def]phenanthrenyl or 11H-benzo[b]fluorenyl (the ring namesand numbering systems are shown below), ##STR5## suitably R¹ is ##STR6##wherein R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH,

R¹⁷ is hydrogen, C₁₋₃ alkyl or CH₂ OH,

R¹⁸ is hydrogen or methyl.

Preferably Ar is naphthacenyl, benz[a]anthracenyl,11H-benzo[b]fluorenyl, acephenanthrylenyl or4,5-dihydroacephenanthrylenyl; preferably R¹⁶ is CH₂ OH or CH(CH₃)OH;R¹⁷ is hydrogen, methyl, ethyl or CH₂ OH.

Most preferably Ar is 5-naphthacenyl, benz[a]anthracen-7-yl,6-acephenanthrylenyl 4,5-dihydro-6-acephenanthrylen-6-yl or11H-benzo[b]fluoren-5-yl; most preferably R¹ is a diol of the structure##STR7## wherein R¹⁹ is hydrogen or methyl and R²⁰ is hydrogen, methylor ethyl, preferably methyl.

Acid addition salts included within the scope of the present inventionare those of compound of formula (I) and ethers and esters thereof.

Esters and nonpharmaceutically useful acid addition salts of thecompounds of the formula (I) are useful intermediates in the preparationand purification of compounds of the formula (I) and pharmaceuticallyuseful acid addition salts thereof, and are therefore within the scopeof the present invention. Thus, acid addition salts of the compounds ofthe formula (I) useful in the present invention include but are notlimited to those derived from inorganic acids, such as hydrochloric,hydrobromic, sulfuric and phosphoric acids, organic acids such asisethionic (2-hydroxyethylsulfonic), maleic, malonic, succinic,salicylic, tartaric, lactic, citric, formic, lactobionic, pantothenic,methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluensulfonic,naphthalene-2-sulfonic, and ascorbic acids, and amino acids such asglycine.

Acid addition salts particularly useful as biocidal agents are thosethat are pharmacologically and pharmaceutically acceptable. Thus,suitable acid addition salts include but are not limited to thosederived from hydrochloric, methanesulfonic, ethanesulfonic, isethionic,lactic, and citric acids.

The preferred pharmacologically and pharmaceutically acceptable acidaddition salts are those that are soluble in solvents suitable forparenteral administration, for example, hydrochlorides,methanesulfonates and isethionates.

Esters of compounds of formula (I) are derived from acids known to thoseskilled in the art to be suitable for ester formation, and areconveniently those derived from C₁₋₆ alkanoic acids or alkanoic acidderivatives, for example acetic acid, propionic acid, n-butyric acid andiso-butyric acid. The esters may be formed from all or only some of thehydroxy groups contained in the compounds of formula (I). Specificcompounds within the scope of formula (I) include;

2[(Benz[a]anthraceny-7-lmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[a]pyren-6-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(5-Naphthacenylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(11H-Benzo[b]fluoren-5-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[[(12-Chloro-5-naphthacenyl)methyl]amino]-2-methyl-1,3-propanediol,

2-[(6-Acephenanthrylenylmethyl)amino]-2-methyl-1,3-propanediol,

2-[[(4,5-Dihydro-6-acephenanthrenyl)methyl]amino]-2-methyl-1,3-propanediol,

2-[(Benz[a]anthracen-3-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(4H-Cyclopenta[def]phenanthren-1-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(Benzo[c]phenanthren-5-ylmethyl)amino]-2-methyl-1,3-propanediol;

ethers, esters thereof; acid addition salts thereof.

Of these specific examples of compounds of formula (I), the preferredcompounds are

2-[(Benz[a]anthracen-7-ylmethyl)amino]-2-methyl-1,3-propanediol and

2-[(11H-Benzo[b]fluoren-5-ylmethyl)amino]-2-methyl-1,3-propanediol,

2-[(6-Acephenanthrylenylmethyl)amino]-2-methyl-1,3-propanediol,

2-[[(4,5-Dihydro-6-acephenanthrylenyl)methyl]amino]-2-methyl-1,3-propanediol;

ethers, esters thereof; acid addition salts thereof.

The compounds of formula (I) and their ethers, esters and acid additionsalts thereof may be prepared by any method known in the art for thepreparation of compounds of analogous structure. Thus, the compounds offormula (I) may, for example, be prepared by any of the methods definedbelow.

1. The reduction of a compound of formula (II) ##STR8## wherein R² -R⁴and R⁶ -R¹⁴ and m are as hereinbefore defined or a suitably protectedderivative thereof followed by deprotection where appropriate.

The conditions and reagents for such a reaction are well known to thoseskilled in the art, and any such conditions/reagents may be employed.The conversion of (II) or suitably protected derivatives thereof may becarried out by a reducing agent followed by deprotection if necessary.The reduction is conveniently carried out by a metal hydride such aslithium aluminum hydride, sodium borohydride, sodium cyanoborohydride,or by catalytic hydrogenation, conveniently by hydrogen in the presenceof a metal catalyst such as palladium or platinum, or equivalentreagents as outlined by J. March, Advanced Organic Chemistry, 2nd ed.,pages 819-820, McGraw Hill, New York, 1977. The reduction is suitablycarried out with the compound of formula (II) in solution in an inertsolvent or mixture of solvents compatible with the reducing agent, at anon-extreme temperature, for example, between 0° and 80° C.,conveniently at room temperature.

In the case of lithium aluminum hydride and like reagents, suitablesolvents include ethers (for example tetrahydrofuran, diethyl ether and1,2-dimethoxyethane) optionally in the presence of a hydrocarboncosolvent (for example toluene, benzene or hexane).

In the case of sodium borohydride and like reagents, suitable solventsinclude alcohols (for example ethanol, methanol or isopropanol)optionally in the presence of a hydrocarbon cosolvent (for exampletoluene, benzene or hexane) or an ether cosolvent (for example diethylether or tetrahydrofuran).

In the case of sodium cyanoborohydride and like reagents, suitablesolvents include those described for sodium borohydride and in thepresence of an acid conveniently glacial acetic acid or ethanolichydrochloric acid as outlined in, for example, R. Hutchins et al.,Organic Preparations and Procedures International 11, 201 (1979).

In the case of catalytic hydrogenation, suitable solvents includealcohols (for example methanol and ethanol) optionally in the presenceof a hydrocarbon cosolvent (for example toluene or benzene) or ethercosolvent (for example diethyl ether or tetrahydrofuran) in the presenceof an acid (for example glacial acetic acid or ethanolic hydrochloricacid) or in glacial acetic acid.

Protected derivatives of compounds of formula (II) are conveniently usedwhen lithium aluminum hydride is employed as the reducing agent.Convenient protecting groups are compatible with the reducing agentutilized and are readily removed under nondestructive conditions, forexample benzyl, tetrahydropyranyl and isopropylidene ethers.

It is often convenient not to isolate the compound of the formula (II)but to react a compound of the formula (III) with a compound of theformula (IV): ##STR9## wherein Ar and R² -R⁴ and R⁶ -R¹⁴ and m are asdefined in (I), and reduce the compound of the formula (II) so formed insitu. The reaction of the compounds of the formulae (III) and (IV) isagain suitably carried out using conditions and reagents which are wellknown to those skilled in the art, for example in the presence of anacid, such as a sulfonic acid, i.e., p-toluenesulfonic acid, in anappropriate inert solvent, such as an aromatic hydrocarbon, suitablytoluene, with azeotropic removal of water followed by treatment with thereducing agent in an appropriate solvent, suitably ethanol or methanol.Alternatively, (II) formed under equilibrium conditions in appropriatesolvents can be reduced in situ with an appropriate reducing agent,suitably sodium cyanoborohydride. The compound of formula (III) may bein the form of a protected aldehyde, for example an acetal, whichliberates the aldehyde function under the reaction conditions.

In turn, a compound of formula (III) can be synthesized by reacting theappropriate polycarbocyclic ring system with a formylating agent such asthat generated by the reaction between SnCl₄ and Cl₂ CHOCH₃ orequivalent reagents, for example, according to the method of A. Riecheet al., Chem. Ber. 93, 88 (1960), or with other standard formylatingreagents/procedures known to the art, for example, the Gatterman-Koch(CO/HCl/AlCl₃ /CuCl, the Gatterman reaction (HCN/HCl/ZnCl₂), and theVilsmeier reaction (POCl₃ /PhN(Me)CHO, or POCl₃ /Me₂ NCHO) (J. March,vide supra, pages 494-497).

The compounds of the formula (III) may also be prepared from anappropriate polycarbocyclic ring system substituted by a suitablefunctional group such as (but not limited to) esters, CH₂ OH, CHBr₂,CH₃, COCH₃, COOH, or CN, and converting this functional group to analdehyde group by methods well known to those skilled in the art.

Where the polycarbocyclic ring system bears substituents, the compoundof formula (III) may be prepared by a variety of methods known in theart of organic chemistry depending on the nature of the substituent onthe polycyclic ring. For example, if the substituent(s) is a halogen,the starting materials may be prepared by direct treatment of theappropriate polycarbocyclic ring system with a halogenating agent (e.g.,Cl₂, Br₂, or SO₂ Cl₂) or indirectly by such routes as the Sandmeyerreaction (H. H. Hodgson, Chem. Rev. 40, 251 (1947). If thesubstituent(s) is alkyl, the polycarbocyclic ring system may be reactedwith the appropriate reagents under Friedel-Crafts reaction conditions(G. A. Olah, Friedel Crafts and Related Reactions, Vols. 1-3,Interscience, New York, NY, 1963-1965).

In appropriate cases, the compounds of the formula (IV) and ethersthereof also may be prepared by methods known in the art, for example,by the reaction of a compound of the formula (V) ##STR10## (or ethersthereof) where R⁷⁻⁹ and R¹¹ -R¹⁴ and m are as hereinbefore defined withan appropriate aldehyde, conveniently acetaldehyde or formaldehyde (asin B. M. Vanderbilt and H. B. Hass, Ind. Eng. Chem. 32, 34 (1940))followed by reduction (as outlined in J. March, vide supra, pages1125-1126), conveniently by hydrogen and a metal catalyst (for example,a platinum containing catalyst) in an appropriate solvent, convenientlyglacial acetic acid.

2. The reduction of a compound of the formula (VI) ##STR11## wherein Arand R² -R¹⁴ and mare as hereinbefore defined and the hydroxy groups areoptionally protected, followed by deprotection of the hydroxy groupswhere appropriate. The reduction may be carried out by standard reducingagents known for carrying out this type of reduction (as outlined in J.March, vide supra, page 1122), for example, a hydride reagent such aslithium aluminium hydride in an inert solvent, such as an ether, i.e.,tetrahydrofuran, at a non-extreme temperature, for example, at between0° and 100° C. and conveniently at the reflux temperature of the ether.The compound of the formula (VI) may be formed by the reaction of theappropriate acid (ArCOOH) or a suitable reactive acid derivative thereof(as outlined in J. March, vide supra, pages 382-390), for example, anacid halide, in an inert solvent with an amine of the formula (IV) inwhich the hydroxy groups are optionally protected, for example, when thecompound of the formula (IV) is a diol, by an isopropylidene group. Thecompound of the formula (VI) so formed is suitably reduced in situ anddeprotected if necessary to give a compound of formula (I). Thecompounds of the formula ArCOOH can be prepared by methods well known tothose skilled in the art.

3. The reaction of a compound ArCH₂ L (wherein Ar is as hereinbeforedefined and L is a leaving group) with a compound of the formula (IV) ashereinbefore defined. Suitable leaving groups are those defined by J.March, vide supra, pages 325-331, and include halogens such as chlorineand bromine and sulfonic acid derivatives such as p-toluenesulfonate.The reaction is suitably carried out in an appropriate solvent, such asa dipolar aprotic solvent or alcohol at a non-extreme temperature, forexample 50°-100°. The compounds of the formula ArCH₂ L can be preparedby methods well known to those skilled in the art.

There is therefore provided, as a further aspect of the invention, amethod for the preparation of a compound of formula (I) comprising anymethod known for the preparation of analogous compounds, in particularthose methods defined in (1) to (3) hereinabove.

The compounds of this invention have biocidal activity, e.g., are toxicto certain living cells which are detrimental to mammals, for examplepathogenic organisms and tumor cells. While the compounds herein havebiocidal activity, it should be appreciated that the range and level ofactivity may vary from compound to compound, and therefore the compoundsare not necessarily equivalent.

This toxicity to pathogenic organisms has been demonstrated by activityagainst viruses (e.g., Herpes simplex 1/vero), fungi (e.g., Candidaalbicans), protozoa (e.g., Eimeria tenella and Trichomonas vaginalis),bacteria (e.g., Mycoplasma smegmatis and Streptococcus pyrogenes), andhelminths (e.g., Nippostrongylus brasiliensis). The antitumor activityof compounds of formula (I) has been demonstrated in a number ofrecognized screens and primarily by activity against ascitic P388/0leukemia.

Preferred compounds of the formula (I) are those which have antitumoractivity. The activity against ascitic tumors, including P388/0, isevidenced by reduction of tumor cell number in mammals (for example,mice bearing ascitic tumors) and consequent increase in survivalduration as compared to an untreated tumor-bearing control group.Antitumor activity is further evidenced by measurable reduction in thesize of solid tumors following treatment of mammals with the compoundsof this invention compared to the tumors of untreated controltumor-bearing animals. Compounds of formula (I) are active againstmurine tumors such as lymphocytic leukemia P388/0, lymphocytic leukemiaL1210, melanotic melanoma B16, P815 mastocytoma, MDAY/D2 fibrosarcoma,colon 38 adenocarcinoma, M5076 rhabdomyosarcoma and Lewis lungcarcinoma.

Activity in one or more of these tumor tests has been reported to beindicative of antitumor activity in man (A. Goldin et al., in Methods inCancer Research ed. V. T. DeVita Jr. and H. Busch, 16 165, AcademicPress, N.Y. 1979).

There are sublines of P388/0 which have been made resistant to thefollowing clinically useful agents: cytosine arabinoside, doxorubicin,cyclophosphamide, L-phenylalanine mustard, methotrexate, 5-fluorouracil,actinomycin D, cis-platin and bis-chloroethylnitrosourea. Compounds ofthis invention show potent activity against these drug-resistant tumorsusing the procedure for P388/0 above.

Compounds of formula (I) have also been found to be active against humantumor cells in primary cultures of lung, ovary, breast, renal, melanoma,unknown primay, gastric, pancreatic, mesothelioma, myeloma, and coloncancer. As used herein "cancer" is to be taken as synonymous with"malignant tumor" or more generally "tumor" unless otherwise noted. Thisis a procedure in which the prevention of tumor cell colony formation,i.e., tumor cell replication, by a drug has been shown to correlate withclinical antitumor activity in man (D. D. Von Hoff et al., CancerChemotherapy and Pharmacology 6, 265 (1980); S. Salmon and D. D. VonHoff, Seminars in Oncology, 8, 377 (1981)).

Compounds of formula I which have been found to have antitumor activityintercalate in vitro with DNA (this property is determined byviscometric methods using the procedure of W. D. Wilson et al., NucleicAcids Research 4, 2697 (1954)) and a log P as calculated by the methodof C. Hansch and A. Leo in Substituent Constants for CorrelationAnalysis in Chemistry and Biology, John Wiley and Sons, New York, 1979,lying in the range between -2.0 and +2.5.

As has been described above, the compounds of the present invention areuseful for the treatment of animals (including humans) bearingsusceptible tumors. The invention thus further provides a method for thetreatment of tumors in animals, including mammals, especially humans,which comprises the administration of a clinically useful amount ofcompound of formula (I) in a pharmaceutically useful form, once orseveral times a day or other appropriate schedule, orally, rectally,parenterally, or applied topically.

In addition, there is provided as a further, or alternative, aspect ofthe invention, a compound of formula (I) for use in therapy, for exampleas an antitumor agent.

The amount of compound of formula (I) required to be effective as abiocidal agent will, of course, vary and is ultimately at the discretionof the medical or veterinary practitioner. The factors to be consideredinclude the condition being treated, the route of administration, thenature of the formulation, the mammal's body weight, surface area, ageand general condition, and the particular compound to be administered. Asuitable effective antitumor dose is in the range of about 0.1 to about120 mg/kg body weight, preferably in the range of about 1.5 to 50 mg/kg,for example 10 to 30 mg/kg. The total daily dose may be given as asingle dose, multiple doses, e.g., two to six times per day, or byintravenous infusion for a selected duration. For example, for a 75 kgmammal, the dose range would be about 8 to 9000 mg per day, and atypical dose would be about 2000 mg per day. If discrete multiple dosesare indicated, treatment might typically be 500 mg of a compound offormula I given 4 times per day in a pharmaceutically usefulformulation.

While it is possible for the active compound (defined herein as compoundof formula (I), or ether, ester, or salt thereof) to be adminsteredalone, it is preferable to present the active compound in apharmaceutical formulation. Formulations of the present invention, formedical use, comprise an active compound together with one or morepharmaceutically acceptable carriers thereof and optionally othertherapeutical ingredients. The carrier(s) must be pharmaceuticallyacceptable in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient thereof.

The present invention, therefore, further provides a pharmaceuticalformulation comprising a compound of formula (I) (in the form of thefree base, ether, or ester derivative or a pharmaceutically acceptableacid addition salt thereof) together with a pharmaceutically acceptablecarrier therefor.

There is also provided a method for the preparation of a pharmaceuticalformulation comprising bringing into association a compound of formula(I), an ether, ester, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier therefor.

While the antitumor activity of the compounds of formula (I) is believedto reside in the free base, it is often convenient to administer an acidaddition salt of a compound of formula (I).

The formulations include those suitable for oral, rectal or parenteral(including subcutaneous, intramuscular and intravenous) administration.Preferred are those suitable for oral or parenteral administration.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active compound intoassociation with a carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active compound into association with a liquidcarrier or a finely divided solid carrier or both and then, ifnecessary, shaping the product into desired formulations.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, tablets orlozenges, each containing a predetermined amount of the active compound;as a powder or granules; or a suspension in an aqueous liquid ornon-aqueous liquid such as a syrup, an elixir, an emulsion or a draught.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active compound in a free-flowingform such as a powder or granules, optionally mixed with a binder,lubricant, inert diluent, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine, a mixture of thepowdered active compound with any suitable carrier.

A syrup may be made by adding the active compound to a concentrated,aqueous solution of a sugar, for example sucrose, to which may also beadded any accessory ingredients. Such accessory ingredient(s) mayinclude flavorings, an agent to retard crystallization of the sugar oran agent to increase the solubility of any other ingredient, such as apolyhydric alcohol for example glycerol or sorbitol.

Formulations for rectal administration may be presented as a suppositorywith a conventional carrier such as cocoa butter.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active compound which ispreferably isotonic with the blood of the recipient. Such formulationssuitably comprise a solution of a pharmaceutically and pharmacologicallyacceptable acid addition salt of a compound of the formula (I) that isisotonic with the blood of the recipient. Thus, such formulations mayconveniently contain distilled water, 5% dextrose in distilled water orsaline and a pharmaceutically and pharmacologically acceptable acidaddition salt of a compound of the formula (I) that has an appropriatesolubility in these solvents, for example the hydrochloride, isethionateand methanesulfonate salts, preferably the latter.

Useful formulations also comprise concentrated solutions or solidscontaining the compound of formula (I) which upon dilution with anappropriate solvent give a solution suitable for parental administrationabove.

In addition to the aforementiond ingredients, the formulations of thisinvention may further include one or more accessory ingredient(s)selected from diluents, buffers, flavoring agents, binders, surfaceactive agents, thickeners, lubricants, preservatives (includingantioxidants) and the like.

The following examples are provided by the way of illustration of thepresent invention and should in no way be construed as a limitationthereof.

General Comments

All solvents were reagent grade and used without further purificationwith the following exceptions. THF was dried by distillation from Na/Kalloy under nitrogen (N₂) and used immediately. Toluene (PhCH₃) wasdistilled from CaH₂ under N₂ and stored over 3 Å molecular sieves.Chemicals used were reagent grade and used without purification unlessnoted. The full name and address of the suppliers of the reagents andchemicals is given when first cited. After this, an abbreviated name isused.

Preparative HPLC was carried out on a Water's Prep LC/System 500Amachine using two 500 g silica gel (SiO₂) cartridges unless otherwisenoted. Plugs of SiO₂ used for purifications were "flash chromatography"SiO₂ (Merck & Co., Inc., Merck Chemical Division, Rahway, NJ, 07065,Silica Gel 60, 230-400 mesh). In this procedure, an appropriate volumesintered glass funnel was filled approximately 3/4 full with the SiO₂and packed evenly by tapping the outside of the funnel. A piece offilter paper was then placed on top of the SiO₂ and a solution of thematerial to be purified applied evenly to the top. Gentle suctionthrough a filter flask moved the eluting solvent through the plugrapidly. The appropriate size fractions were combined as needed andfurther manipulated.

General procedures are described in detail. Analogous procedures showmelting point (mp), recrystallization solvents, and elemental analyses(all elements analyzing within a difference of ≦0.4% of the expectedvalue). Any changes to the procedure such as solvent, reactiontemperature, reaction time, or workup are noted.

NMR (¹ H, ¹³ C), IR and MS data of all new products were consistent withthe expected and proposed structures. The positions assigned tostructural isomers were unequivocally determined by a number of NMRtechniques. All final products were dried in a vacuum oven at 20 mm Hgpressure at the temperature indicated overnight (12-16 h). Alltemperatures are in degrees Celsius. Other abbreviations used are: roomtemperature (RT), absolute (abs.), round bottom flask (RB flask),minutes (min), hours (h).

EXAMPLE 12-[(Benz[a]anthracen-6-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

To a 3-necked RB flask equipped with magnetic stirring bar, condenser,thermometer, Dean-Stark trap, and N₂ inlet line with bubbler was addedbenz[a]anthracene-7-carbaldehyde (Cambridge Chemical, Inc., 202 E. SmithSt., Milwaukee, WI 53207, 5.13 g, 20 mmol),2-amino-2-methyl-1,3-propanediol (Aldrich Chemical Co., P.O. Box 2060 ,Milwaukee, WI 53201, 4.20 g, 40 mmol), p-toluenesulfonic acidmonohydrate (Aldrich, 0.1 g), and PhCH₃ (250 mL). The mixture wasstirred at reflux with removal of H₂ O for 3 h (or in the case of otherexamples until no H₂ O is collected). Most of the PhCH₃ was then removedby distillation. The mixture was then cooled in an ice bath and dilutedwith abs. EtOH (200 mL) and further cooled. Solid NaBH₄ (MCBManufacturing Chemists, Inc., 2909 Highland Ave., Cincinnati, OH 45212,1.51 g, 40 mmol) was added in one portion to the reaction mixture. Theice bath was then removed, the reaction mixture allowed to warm to RTand further stirred overnight. The reaction was then basified with 1NNaOH (2 L). The white solid which formed was filtered, washed with H₂ O(4 L), and sucked semidry. The solid was then dissolved in a mixture ofabs. EtOH (100 mL) and CH₃ SO₃ H (99.5%, Morton Thiokol, Inc.-AlfaProducts, P.O. Box 299, 152 Andover Street, Danvers, MA 01923, 3 mL),filtered and diluted to 2 L with Et₂ O. After filtration, two additionalcrystallizations (EtOH/Et₂ O) and drying, 7.48 g (84.7%) of2-[(benz[a]anthracen-7-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate was obtained, mp 233°-234° (dec), (C, H, N, S).

In other analogous procedures the solvent was removed by rotaryevaporation before the addition of 1N NaOH or alternatively, H₂ O. Thecrude wet product can also be dried at 100° overnight in a vacuum ovento remove most of the H₂ O before salt formation. Additionally, i-PrOHand CH₃ OH can be used in combination with Et₂ O or hexane as therecrystallization solvent for these salts.

EXAMPLE 2 2-[(Benzo[a]pyren-6-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.25H₂ O

Using the reductive amination procedure outlined in Example 1,benzo[a]pyrene-6-carbaldehyde (Cambridge Chemical, Inc.) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave2-[(benzo[a]pyren-6-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.25H₂ O in 53.1% yield, mp darkens >195°, 275° (dec),(C, H, N, S).

EXAMPLE 3 2-[(5-Naphthacenylmethyl)amino]-2-methyl-1,3-propanediol 3A.Naphthacene-5-carbaldehyde and 3B. Naphthacene-5,11-dicarbaldehyde

To a 3-necked RB flask equipped with overhead mechanical stirrer,condenser, addition funnel, N₂ inlet line with bubbler was addedN-methylformanilide (Aldrich, 89.21 g, 0.66 mol, 81 mL) ando-dichlorobenzene (Aldrich, 200 mL). The mixture was cooled to 10° withan ice bath. Phosphorus oxychloride (Aldrich, 101.21 g, 0.66 mol, 60 mL)was then added dropwise to the solution not allowing the reactiontemperature to rise above 10°. The reaction mixture was then allowed towarm to RT. Solid naphthacene (Cambridge Chemical, Inc., 50 g, 0.22 mol)was then added in five portions over 5 min. The reaction mixture waswarmed slowly to 80° (the mixture turns from purple to an almost blackcolor). The reaction was stirred at 80° for 12 h, cooled, poured intoice water (2 L) and stirred an additional 12 h at RT. The mixture wasthen filtered. The organic layer in the filtrate was dried (Na₂ SO₄) andapplied to a plug of SiO₂ (500 g) and eluted first with PhCH₃ followedby CH₂ Cl₂. The appropriate fractions were combined and the solventremoved by rotary evaporation. Recrystallization (CH₂ Cl₂ /EtOAc) gave17.5 g (31.1% yield) of naphthacene-5-carbaldehyde, mp 163°-164° (Lit.164°, N. P. Buu-Hoi et al., Recueil 76 674 (1957)), (C, H). The solidfrom the filtration of the crude reaction mixture was washed with alarge volume of CH₃ OH (5×200 mL), dissolved in THF (4 L) and passedthrough a plug of SiO₂ (500 g) using an additional 2 L of THF as elutingsolvent. The solvent was reduced to a volume of 300 mL and then dilutedto 800 mL with EtOAc. The solvent volume was reduced to 250 mL. Afterfiltration and drying 10.90 g (17.4% yield) ofnaphthacene-5,11-dicarbaldehyde, mp 247°-250°, (C, H).

3C. 2[(5-Naphthacenylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure described in Example 1,naphthacene-5-carbaldehyde (3A) and 2-amino-2-methyl-1,3-propanediol(Aldrich) gave 50.1% yield of2-[(5-naphthacenylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonte, mp 197.5°-199°, (EtOH/Et₂ O), (C, H, N, S).

EXAMPLE 42-[(11H-Benzo[b]fluroen-5-ylmethyl)amino]-2-methyl-1,3-propanediol 4A.11H-Benzo[b]fluorene-5-carbaldehyde

11H-Benzo[b]fluorene (Cambridge Chemical, Inc.) was formylated using theprocedure of A. Rieche et al., Chem. Ber. 93, 88 (1980). The crudealdehyde appeared to be mainly one isomer by TLC. The crude material waspassed through a plug of SiO₂ using PhCH₃ as the eluting solvent.Removal of the solvent and crystallization (CH₂ Cl₂ /hexane) gave an 86%yield of 11H-benzo[b]fluorene-5-carbaldehyde, mp 104.5°-106.5°, (C, H).

4B. 2-[(11H-Benzo[b]fluroen-5-ylmethyl)amino]-2methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in 1,11H-benzo[b]fluorene-5-carbaldehyde (4A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 49.6% yield of2-[(11H-benzo[b]fluoren-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 211°-213°, (C, H, N, S).

EXAMPLE 52-[(Benzo[c]phenanthren-5-ylmethyl)amino]-2-methyl-1,3-propanediol 5A.Benzo[c]phenanthrene-5-carbaldehyde

Benzo[c]phenanthrene (Cambridge Chemical, Inc.) was formylated using theprocedure of A. Rieche et al., Chem. Ber. 93, 88 (1980). The crudealdehyde appeared to be mainly one isomer by TLC. The crude material waspurified on a plug of SiO₂ using PhCH₃ as the eluting solvent followedby recrystallization (CH₂ Cl₂ /hexane) and gave pure material (74%yield) isomerically pure by NMR shown to bebenzo[c]phenanthrene-5-carbaldehyde, mp 133°-134°, (C, H).

5B. 2-[(Benzo[c]phenanthren-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethansulfonate

Using the reductive amination procedure described in Example 1,benzo[c]phenanthrene-4-carbaldehyde (5A) and2-amino-2-methyl-propanediol (Aldrich) gave 57.5% of2-[(benzo[c]phenanthren-5-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 205°-207° (dec), (EtOH/Et₂ O), (C, H, N, S).

EXAMPLE 62-[[(12-Chloro-5-naphthacenyl)methyl]amino]-2-methyl-1,3-propanediol 6A.12-Chloronaphthacene-5-carbaldehyde

To a 3-necked RB flask equipped with overhead stirrer, condenser,addition funnel, and N₂ inlet line with bubbler was added2,3-benz-9-anthrone (prepared by the procedure of L. F. Fieser et al.,J. Amer. Chem. Soc. 53, 2329 (1931), 57.3 g, 0.235 mol) and DMF(Aldrich, 400 mL). The mixture was cooled to 0°. Phosphorus oxychloride(MCB, 167.5 g, 1.09 mol, 100 mL) was then added dropwise to the flaskwhile reaction temperature was maintained between 0°-10° over a periodof 1.5 h. The reaction color deepended to a dark purple as the reactiontemperature was slowly raised to 85°. The reaction was stirred at thistemperature for 2 h, cooled and then stirred at RT overnight. Thereaction mixture was poured into 2 L of 2.8M NaOAc, vigorously stirredfor 30 min, then filtered. The dark purple solid was washed with H₂ O (1L) then with CH₃ OH (3×500 mL). After drying in a vacuum (40°) overnight63.9 g (97.6%) of 12-chloronaphthacene-5-carbaldehyde was obtained whichwas used without further purification. An analytical sample wasrecrystallized from CH₂ Cl₂ /CH₃ OH; mp 211.5°-213.5°, (C, H).

6B. 2-[[(12-Chloro-5-naphthacenyl)methyl]amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in Example 1,12-chloronaphthacene-5-carbaldehyde (6A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave 31.8% yield of2-[[(12-chloro-5-naphthacenyl)methyl]amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 219°-220° (dec), (CH₃ OH/Et₂ O), (C, H, N, Cl, S).

6C. 2-[[(12-Chloro-5-naphthacenyl)methyl]amino]-2-methyl-1,3-propanediolhydrochloride

Using the reductive amination procedure outlined in Example 1 exceptthat the crude free base was dissolved in ethanolic HCl,12-chloronaphthacene-5-carbaldehyde (6A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 38.6% yield of2-[[(12-chloro-5-naphthacenyl)methyl]amino]-2-methyl-1,3-propanediolhydrochloride, mp >300°, (CH₃ OH/Et₂ O), (C, H, N, Cl).

EXAMPLE 72-[(Benz[a]anthracen-3-ylmethyl)amino]-2-methyl-1,3-propanediol 7A.5,6,8,9,10,11-Hexahydrobenz[a]anthracene-3-carbaldehyde

5,6,8,9,10,11-Hexahydrobenz[a]anthracene (Cambridge Chemicals, Inc. 38.0g, 0.162 mol) was formylated using the procedure of A. Rieche et al.,(Chem. Ber. 93, 88 (1960)). The crude aldehyde mixture was passedthrough a 40×10 cm plug of SiO₂ using PhCH₃ as the eluting solvent.Three aldehyde fractions were isolated. The least mobile of thefractions by TLC contained 11.23 g (26.5% yield) of crude5,6,8,9,10,11-hexahydrobenz[a]anthracene-3-carbaldehyde (identified by ¹H-NMR) which was used directly without further purification.

7B. Benz[a]anthracene-3-carbaldehyde

To a RB flask equipped with magnetic stirring bar, reflux condenser andN₂ inlet line with bubbler added5,6,8,9,10,11-hexahydrobenz[a]anthracene-3-carbaldehyde (7A, 10.41 g,39.7 mmol), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (Aldrich,27.02 g, 0.119 mol) and dry PhCH₃ (500 mL). The mixture was refluxed for2 h until no more starting material remained by TLC, cooled and filteredto give a deep red solution. The solution was applied to a 40×10 cmcolumn of SiO₂ and eluted with additional PhCH₃ as the solvent. Theappropriate fractions were combined and the solvent removed to give 6.01g of crude material. This was crystallized twice from PhCH₃ /hexane(1:4) and dried to give 2.94 g (28.9% yield) ofbenz[a]anthracene-3-carbaldehyde, mp 144°-145°, (C, H).

7C. 2-([Benz[a]anthracen-3-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in Example 1,benz[a]anthracene-3-carbaldehyde (7B) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 52.7% yield of2-[(benz[a]anthracen-3-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 189°-191.5°, (C, H, N, S) (i-PrOH/Et₂ O).

EXAMPLE 82-[(4H-Cyclopenta[def]phenanthren-1-ylmethyl)amino]-2-methyl-1,3-propanediol8A. 4H-Cyclopenta[def]phenanthrene-1-carbaldehyde

4H-Cyclopenta[def]phenanthrene (Aldrich) was formylated using theprocedure of A. Rieche et al., (Chem. Ber. 93, 88 (1960)). The crudealdehyde was passed through a plug of silica gel using CH₂ Cl₂ as theeluting solvent. The appropriate fractions were combined and the solventremoved to give 48 g of product. This was recrystallized from hexane togive 28.1 g (53.6% yield) of pure4H-cyclopenta[def]phenanthrene-1-carbaldehyde, mp 209°-212°, (C, H).

8B.2-[(4H-Cyclopenta[def]phenanthren-1-ylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate.0.05 i-PrOH

Using the reductive amination procedure outlined in Example 1,4H-cyclopenta[def]phenanthrene-1-carbaldehyde (8A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 10% yield of2-[(4H-cyclopenta[def]phenanthren-1-ylmethyl)amino]-2-methyl-1,3-propanediolmethansulfonate 0.05 i-PrOH, mp 160°-162°, (C, H, N, S) (EtOH/Et₂ O).

EXAMPLE 92-[[(4,5-Dihydro-6-acephenanthrylenyl)methyl]amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in Example 1,4,5-dihydro-6-acephenanthrylenecarbaldehyde (J. P. Hoeffinger, P.Jacquignon, and N. P. Buu-Hoi, Bull. Soc. Chim. Fr. 974 (1970)) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave 74% yield of2-[[(4,5-dihydro-6-acephenanthrylenyl)methyl]amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 240°-242° (dec), (C, H, N, S) (EtOH/hexane).

EXAMPLE 102-[(6-Acephenanthrylenylmethyl)amino]-2-methyl-1,3-propanediol 10A.Acephenanthrylene-6-carbaldehyde

Using the dehydrogenation procedure outlined in Example 7B,4,5-dihydroacephenanthrylene-6-carbaldehyde (J. P. Hoeffinger, P.Jacquignon, and N. P. Buu-Hoi, Bull. Soc. Chim. Fr. 974 (1970)) gave a35.8% yield of 6-acephenanthrylenecarbaldehyde, mp 161°-163° (dec), (C,H), (PhCH₃ /hexane).

10B. 2-[(6-Acephenanthrylenylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate

Using the reductive amination procedure outlined in Example 1,acephenanthrylene-6-carbaldehyde (10A) and2-amino-2-methyl-1,3-propanediol (Aldrich) gave a 61.5% yield of2-[(6-acephenanthrylenylmethyl)amino]-2-methyl-1,3-propanediolmethanesulfonate, mp 232°-233° (dec), (C, H, N, S) (EtOH/Et₂ O).

Antitumor Screening Results

Methods for evaluating the antitumor activity of these compounds areessentially those used in the Tumor Panel by the DevelopmentalTherapeutics Program, Division of Cancer Treatment, National CancerInstitute, A. Goldin, et al., Methods in Cancer Research, Vol. XVI, p.165, Academic Press (1979). Some modifications, in dose level andschedule have been made to increase the testing efficiency.

EXAMPLE 11 Lymphocytic Leukemia P388/0 Test

CD2-F₁ mice, of the same sex, weighing 20±3 g, are used for this test.Control and test animals are injected intraperitoneally with asuspension of -10⁶ viable P388/0 tumor cells on day 0. In each test,several dose levels which bracket the LD₂₀ of the compound areevaluated; each dose level group contains six animals. The testcompounds are prepared either in physiologic saline containing 0.05%Tween 80 or distilled water containing 5% dextrose and are administeredintraperitoneally on days 1, 5, and 9 relative to tumor implant. Dosesare on a mg/kg basis according to individual animals' body weights. Theday of death for each animal is recorded, the median identified for eachgroup and the ratios of median survival time for treated (T)/control (C)groups are calculated. The criterion for activity is T/C×100≧120%.Results of P338/0 testing are summarized in Table I below.

                  TABLE I                                                         ______________________________________                                                 Optimal  T/C × 100%                                            Compound of                                                                            Dose     (Excluding 30                                                                             30 Day  LD.sub.20                               Formula  (mg/kg)  Day Survivors)                                                                            Survivors                                                                             (mg/kg)                                 ______________________________________                                        1        220      +270        2/6     180                                     2        111      +204        0/6     100                                     3C       50       +250        0/6     40                                      4B       225      +280        2/5     250                                     5B       15       +140        0/6     7.5                                     6B       75       +150        0/6     70                                      6C       45       +150        0/6     67.5                                    7C       200      +120        0/6     200                                     8B       30       +145        0/6     225                                     9        60       +215        2/6     50                                      10       110      +270        2/6     100                                     ______________________________________                                    

EXAMPLE 12 Formulation Examples A. TABLET

    ______________________________________                                        Compound of Formula I                                                                             500.0 mg                                                  Pregelatinized Corn Starch                                                                        60.0 mg                                                   Sodium Starch Glycolate                                                                           36.0 mg                                                   Magnesium Stearate   4.0 mg                                                   ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, pregelatinized corn starch and sodium starchglycolate. The powders are wetted with purified water to form granules.The granules are dried and mixed with the magnesium stearate. Theformulation is then compressed into tablets weighing approximately 600mg each.

B. TABLET

    ______________________________________                                        Compound of formula (I)                                                                          500.0 mg                                                   Corn Starch        70.0 mg                                                    Lactose            83.8 mg                                                    Magnesium Stearate  4.2 mg                                                    Polyvinylpyrrolidone                                                                             14.0 mg                                                    Stearic Acid       28.0 mg                                                    ______________________________________                                    

The compound of formula (I) is finely ground and intimately mixed withthe powdered excipients, corn starch and lactose. The powders are wettedwith a solution of polyvinylpyrrolidone dissolved in a mixture ofpurified water and denatured alcohol to form granules. The granules aredried and mixed with the powdered stearic acid and magnesium stearate.The formulation is then compressed into tablets weighing approximately700 mg each.

C. CAPSULES

    ______________________________________                                        Compound of formula (I)                                                                          500.0 mg                                                   Corn Starch        50.0 mg                                                    Magnesium Stearate  3.0 mg                                                    ______________________________________                                    

The finely divided compound of formula (I) is mixed with powdered cornstarch and wetted with denatured alcohol to densify the powder. Thedried powder is mixed with stearic acid and filled into hard-shellgelatin capsules.

D. SYRUP

    ______________________________________                                        Compound of formula (I)                                                                          250.0 mg                                                   Ethanol            250.0 mg                                                   Glycerin           500.0 mg                                                   Sucrose            3,500.0 mg                                                 Flavoring Agent    q.s.                                                       Coloring Agent     q.s.                                                       Preserving Agent   0.1%                                                       Purified Water q.s. to                                                                           5.0 mL                                                     ______________________________________                                    

The compound of formula (I) is dissolved in the ethanol, glycerin, and aportion of the purified water. The sucrose and preserving agent aredissolved in another portion of hot purified water, and then thecolouring agent is added and dissolved. The two solutions are mixed andcooled before the flavoring agent is added. Purified water is added tofinal volume. The resulting syrup is thoroughly mixed.

E. IV INJECTION

    ______________________________________                                        Compound of formula (I)                                                                         5.0 mg                                                      Glycerin          q.s. for isotonicity                                        Preservative      0.1%                                                        Hydrochloric Acid or                                                                            as needed for                                               Sodium Hydroxide  pH adjustment                                               Water for Injection                                                                             q.s. to 1 mL                                                ______________________________________                                    

The compound of formula (I) and preservative is added to the glycerinand a portion of the water for injection. The pH is adjusted withhydrochloric acid or sodium hydroxide. Water for injection is added tofinal volume and solution is complete after thorough mixing. Thesolution is sterilized by filtration through a 0.22 micrometer membranefilter and aseptically filled into sterile 10 mL ampules or vials.

What is claimed is:
 1. A compound of the formula

    ArCH.sub.2 R.sup.1

or a pharmaceutically acceptable acid addition salt thereof wherein R¹contains not more than eight carbon atoms and is a group ##STR12##wherein m is 0 or 1; R⁵ is hydrogen; R⁶ and R⁷ are the same or differentand each is hydrogen or C₁₋₅ alkyl optionally substituted by hydroxy; R⁸and R⁹ are the same or different and each is hydrogen or C₁₋₃ alkyl;##STR13## is a five- or six-membered saturated carbocyclic ring; R¹⁰ ishydrogen, methyl or hydroxymethyl; R¹¹, R¹² and R¹³ are the same ordifferent and each is hydrogen or methyl; R¹⁴ is hydrogen, methyl,hydroxy, or hydroxymethyl and Ar is naphthacene or benzanthracene. 2.The compound or salt of claim 1 in which R¹ is ##STR14## wherein m isO;R¹⁶ is CH₂ OH, CH(CH₃)OH or CH₂ CH₂ OH; R¹⁷ is hydrogen, C₁₋₃ alkyl orCH₂ OH; and R¹⁸ is hydrogen or methyl.
 3. A compound or salt of claim 2wherein R¹⁶ is CH₂ OH or CH(CH₃)OH and R¹⁷ is hydrogen, methyl, ethyl orCH₂ OH.
 4. A compound or salt of claim 1 wherein R¹ is a diol of thestructure ##STR15## wherein R¹⁹ is hydrogen or methyl and R²⁰ ishydrogen, methyl or ethyl.
 5. A compound or salt of claim 4 wherein R²⁰is methyl.
 6. A compound or salt of claim 5 in which R¹⁹ is hydrogen. 7.A compound or salt of claim 5 in which R¹⁹ is methyl.